Abstract

Oral chemotherapy for colorectal cancer (CRC) is limited by poor tumor selectivity and microenvironment-driven resistance. Addressing these limitations demands materials that integrate tumor-selective targeting with immune microenvironment modulation. Here, clinical analysis of CRC specimens revealed pronounced transferrin (Tf) enrichment in CRC-associated intestinal regions. Guided by this finding, we engineered a gastrointestinal-stable cyclic Tf-binding peptide (cp) with high Tf affinity and constructed cp-modified ginger-derived extracellular vesicles (cp-GEVs) for in situ Tf-mediated sandwich-like targeting. By recruiting endogenous Tf, cp-GEVs established a Tf-mediated bridging interface that selectively engages Tf receptor-overexpressing intestinal epithelium and tumor cells, enabling efficient epithelial transcytosis, tumor-selective accumulation, and deep intratumoral penetration after oral administration. When loaded with irinotecan (CPT-11), CPT@cp-GEVs significantly enhanced intracellular drug delivery and reprogrammed immunosuppressive M2-like tumor-associated macrophages toward a pro-inflammatory phenotype, thereby disrupting cancer stem cell-enriched drug-resistant niches. In AOM/DSS-induced primary CRC models and patient-derived ex vivo systems, CPT@cp-GEVs significantly improved chemotherapeutic efficacy while attenuating resistance. Collectively, this work establishes a Tf-mediated sandwich-like targeting framework for oral cancer therapy, offering a conceptually distinct materials design paradigm that integrates endogenous ligand recruitment with immune microenvironment reprogramming.